Effect of Phosphorylation and O-GlcNAcylation on Proline-Rich Domains of Tau. Academic Article uri icon


  • The microtubule-associated protein Tau (MAPT) is a phosphoprotein in neurons of the brain. Aggregation of Tau is the leading cause of tauopathies such as Alzheimer's disease. Tau undergoes several post-translational modifications of which phosphorylation and O-GlcNAcylation are key chemical modifications. Tau aggregates into paired helical filaments and neurofibrillary tangles upon hyperphosphorylation, whereas O-GlcNAcylation stabilizes the soluble form of Tau. How specific phosphorylation and/or O-GlcNAcylation events influence Tau conformations remains largely unknown due to the disordered nature of Tau. In this study, we have investigated the phosphorylation- and O-GlcNAcylation-induced conformational effects on a Tau segment (Tau225-246) from the proline-rich domain (P2), by performing metadynamics simulations. We study two different phosphorylation patterns: Tau225-246, phosphorylated at T231 and S235, and Tau225-246, phosphorylated at T231, S235, S237, and S238. We also study O-GlcNAcylation at T231 and S235. We find that phosphorylation leads to the formation of strong salt-bridge contacts with adjacent lysine and arginine residues, which disrupts the native -sheet structure observed in Tau225-246. We also observe the formation of a transient -helix (238SAKSRLQ244) when Tau225-246 is phosphorylated at four sites. In contrast, O-GlcNAcylation shows only modest structural effects, and the resultant structure resembles the native form of the peptide. Our studies suggest the opposing structural effects of both protein post-translational modifications (PTMs) and the importance of salt bridges in governing the conformational preferences upon phosphorylation, highlighting the role of proximal arginine and lysine upon hyperphosphorylation.

published proceedings

  • J Phys Chem B

altmetric score

  • 13

author list (cited authors)

  • Rani, L., Mittal, J., & Mallajosyula, S. S.

citation count

  • 12

complete list of authors

  • Rani, Lata||Mittal, Jeetain||Mallajosyula, Sairam S

publication date

  • March 2020